Gastroduodenal Dysfunction The Gastroparesis Syndrome

Diabetic gastroparesis is an electromechanical motility disorder that in many instances involves not only the stomach, but also the upper small bowel. The molecular pathophysiology of diabetic gastroparesis is unknown. In fact, a variety of pathogenetic factors may be implicated in most patients. Animal studies point to a defect in the enteric nervous system characterized by a loss of nitric oxide signals from nerves to gut smooth muscle (18,19). Interstitial cells of Cajal might also be disrupted (20). "Vagal denervation" by autonomic neuropathy is probably relevant and in turn might induce changes in postprandial hormone profile, including gastrin levels (21). Prostaglandin overproduction in gastric smooth muscle has been linked to gastric slow-wave disruption (22). Interestingly, in animal models of diabetic gastroparesis there is evidence that homeostatic mechanisms are activated in the enteric nervous system to compensate for the loss of extrinsic innervation (20).

Acute hyperglycemia might play an important pathogenetic role (23). Antral motility decreases with postprandial glucose levels more than 9.7 mmol/L (2). In 10 patients with type 1 diabetes mellitus and sensory motor neuropathy, Flowaczny and coworkers (24) showed that when plasma glucose concentrations were controlled by permanent iv administration of insulin, gastric emptying rates were near normal. Nevertheless, although achieving and sustaining normoglycemia is undoubtedly important, in clinical practice symptomatic patients with gastroparesis still require prokinetic therapy for satisfactory results (2). However, to further complicate matters, it has been shown that the accelerating effect of prokinetics, such as cisapride and erithromycin is in turn significantly dampened by hyperglycemia (25). Thus, good glycemic control is an inevitable premise to successful management of diabetic gastroparesis.

Another possible connection between diabetes mellitus and the GI tract can be infrequent autoimmune disease associated with type 1 diabetes mellitus, such as celiac disease, autoimmune chronic pancreatitis, and autoimmune gastropathy (2). Indeed, about 15-20 of patients with type 1 diabetes mellitus exhibit parietal cell antibodies (26), but on the other hand no clear-cut relationship has been found between parietal cell antibody titers and delayed gastric emptying (26). Finally, the finding of gastroparesis associated with autonomic neuropathy in a diabetic should not preclude the possibility of coexistent mechanical factors contributing to the apparent motor abnormality (27). First assessing the possibility of mechanical obstruction remains a key premise to diagnosing a gut motor disorder under any circumstances.

Clinical Findings and Evaluation

Both acute and chronic gastroparesis are relatively common occurrences (Table 1). Gastric emptying of solids is delayed in 30-50% of patients with diabetes mellitus (23,26,28,29). Another 20% might in fact present accelerated gastric emptying (29). Although, many such patients experience upper GI symptoms that impair their quality of life, others are asymptomatic. Thus, the concept that symptoms are the direct outcome of delayed gastric emptying or conversely that delayed gastric emptying might be associated with clinical symptoms is now recognized as overly simplistic. Lack of correlation between gastric emptying rates and GI symptoms has been evidenced by numerous studies (26). In contrast, the potential impact of gastroparesis on oral drug absorption and blood glucose control in diabetics has probably been underestimated (28). Indeed, gastroparesis should be suspected in individuals with erratic glucose control (23,30) and timing insulin regarding gastric emptying rates might be helpful. A hypothesis has been put forward that improving gastric emptying in diabetics with gastroparesis with the use of prokinetics would regularize duodenal nutrient delivery rates and achieve better glycemic control. Although seemingly logical and attractive, experimental studies in human diabetics have not shown enough supportive evidence to justify it as clinically relevant (31,32).

Gastroparesis affects both type 1 and type 2 forms of diabetes (13). Diabetic neuropathy is present in about two-thirds of gastroparetic patients with type 1 and about one-fifth with type 2 diabetes (2). One study (33) examined the relationship between gastric emptying parameters, gastric symptoms, and cardiovascular autonomic function. In addition, they found no significant relationship between the prevalence of GI symptoms and abnormalities in gastric emptying. Neither there was any significant relationship between delayed gastric emptying and cardiovascular autonomic neuropathy in their group of patients (33).

This is a particularly contentious issue as other studies' results are discrepant. Tomi et al. (29) found an association between abnormalities in gastric emptying (delayed or accelerated) and cardiovascular autonomic neuropathy, although not with symptoms. De Block et al. (26) also found an association between delayed gastric emptying and autonomic nerve function (Ewing tests). Similarly, other investigators (34) found a strong correlation between diabetic gastroparesis and cardiac autonomic denervation, nephropathy, and retinopathy. Huszno et al. (35) also explored the potential concordance between diabetic gastroparesis and cardiovascular neuropathy in 42 subjects with type 1 diabetes mellitus. Their results show a trend toward a higher prevalence of established cardiovascular neuropathy in patients with diabetic gastroparesis as opposed to those with normal or accelerated emptying, but considerable overlap was apparent. These authors concluded that diabetic autonomic neuropathy tends to be disseminated and does not invariably affect and alter the function of a particular organ in the body.

Gastric emptying abnormalities, including both solid and liquid components of a test meal, remain rather stable for long periods of time (mean 12.3 ± 3.1 years of follow-up (SD) in one study [36]). Neither there was much change in the GI symptom pattern during such long follow-up (36). As expected, the prevalence of autonomic neuropathy did increase during the years from an initial 35% at baseline to 80% at follow-up (36).

When it comes to specific abnormalities in upper gut function as responsible for gastroparesis, the thinking has fluctuated considerably during the decades. Antral hypo-motility with failure to grind and propel mixed chyme into the duodenum has been traditionally accepted as a major pathophysiological factor. However, animal models, suggest that proximal gastric hypomotility and pyloric hypercontractility are more relevant (37). Indeed, quite early, in the laboratory it was recognized that some patients with diabetic gastroparesis presented manometric evidence of hyperactivity at the pylorus (Fig. 2) (38). In other patients, delayed gastric emptying might be caused or aggravated by intestinal dysmotility (39). Finally, in some patients with chronic nausea, gastric stasis may be owing in part to centrally relayed reflexes triggered by gastric dysrhythmia or other visceral afferent signals.

When symptomatic, gastroparesis manifests by episodes of nausea and vomiting (fasting as well as postprandial) that are often, but not invariably associated with upper abdominal pain. Dyspeptic symptoms such as early satiety, frequent belching as well as bloating might be present. On abdominal examination, a gastric splash might be detected, but it is rare. The episodes of nausea and vomiting tend to follow a variable course and might be self-limited, recurrent, or unrelenting. In severe cases, the gastro-paresis syndrome might lead to malnutrition or serious complications, such as bleeding from Mallory-Weiss tears secondary to repeated bouts of retching or vomiting. Symptoms tend to be worse during periods of diabetic decompensation and in fact the prototypic patient with symptomatic diabetic gastroparesis has poorly controlled, longstanding, insulin-dependent diabetes. Peripheral neuropathy and other manifestations of autonomic dysfunction (orthostatic hypotension, impotence, bladder dysfunction, sweat abnormality) are frequently, but not invariably associated.

In evaluating a patient with suspected diabetic gastroparesis, gastroduodenoscopy, and at least upper GI radiology should be performed first to exclude pyloric or any other type of mechanical obstruction. A careful history about medications (e.g., psychotropic drugs, anticholinergics, ganglion-blocking agents, and so on) should also be obtained. Radiological signs of gastric stasis, such as dilatation of the stomach with retained food and secretions are useful if present in the absence of demonstrable mechanical lesion. However, the sensitivity of radiology in detecting GI motor dysfunction is low. Therefore, a normal barium series does not exclude diabetic gastric dysmotility.

Fig. 2. Example of pyloric tonic activity recorded manometrically in a patient with diabetic gastroparesis. Note the prolongad tonic closure of the pylorus (pylorospasm). (Reproduced from ref. 38.)

Several methods with higher sensitivity to assess gastric motor function are nowadays available. Gastric emptying time is best evaluated using radioscintigraphic techniques that differentiate between emptying of the solid and the liquid phases of a meal (double-isotope scintigraphy). Measurement of gastric emptying rates by a radionucle-ide study remains the gold standard for assessment of gastroparesis (Fig. 3). Alternatives include the 13C-octanoic acid breath test and ultrasonographic measurement of gastric emptying. The 13C-octanoic acid breath test has been compared with radionucleide emptying test in diabetics (17) and has been shown to constitute a suitable method for diagnostic purposes with good correlation observed between both tests.

Fig. 4. Manometric abnormalities recorded during the postprandial period in a diabetic patient with gastroparesis and diarrea. Note burst activity interrupting the otherwise normal postprandial irregular sustained contractile activity of the small bowel.

Real-time ultrasonographic measurement of gastric emptying of a semisolid meal has also shown a reasonably good correlation with the conventional scintigraphic test (40). The ultrasonographic method does not actually measure disappearance of meal from the stomach, but the reduction in antral cross-sectional area as the stomach empties. Electrogastrography has also been suggested as a diagnostic method for gastric motor disturbances in diabetics, but the evidence is not sufficiently strong to recommend it as a clinical diagnostic tool at this point (41).

Manometry is another useful technique in the assessment of upper gut motility disorders (42). In diabetic gastroparesis there is often absence of normal interdigestive motor cycles in the stomach. This observation might explain the formation of bezoars, as phase III activity plays a role in the evacuation of large (>5 mm) indigestible solids from the stomach (7). However, the most consistent abnormality is antral hypomotility after ingestion of a solid meal. This hypomotility is often characterized by a decreased frequency of phasic pressure waves. In more severe cases, there is also reduced wave amplitude (43).

Other evidence of upper gut dysmotility includes episodes of pylorospasm (prolonged and intense tonic contractions), which were found in 14 out of 24 diabetics with the gastroparesis syndrome (38). Abnormal manometric patterns may not be limited to the stomach. Camilleri and Malagelada (39) observed reduced duodeno-jejunal phasic pressure activity (4 out of 14 patients) and nonpropagated bursts of powerful contractions in the proximal small bowel (9 out of 14 patients) (Fig. 4).

Therapy of Gastroparesis

Treatment of diabetic gastroparesis has two facets: one, treatment of autonomic neuropathy and of hyperglycemia that are major pathogenetic substrates; and two, correction of the motor disorder itself (44). Ruboxistaurin appears as a promising disease-modifying therapy for autonomic neuropathy, currently undergoing phase III trials (45). Epalrestat, an aldose reductase inhibitor used in the treatment of diabetic neuropathy has also shown positive effects on the electrogastrogram of patients with diabetic gastroparesis, but electrogastrography is not considered sufficiently reliable to draw firm conclusions (46). Attempts at correcting the motor disorder might include a variety of nutritional, pharmacological, and electrical stimulation and ancillary methods (44). Dietary measures are important and patients with severe feeding problems might even require surgical implantation of a feeding jejunostomy, sometimes complemented by a "venting" gastrostomy that serves to decompress the gastric cavity on demand (47,48).

Prokinetics (metoclopramide, domperidone, cisapride, cinitrapride, and others) constitute the conventional and standard approach to pharmacotherapy. Prokinetic drugs in combination with dietary measures bring symptomatic relief in most patients (47,49). Nevertheless, it should be remembered that diabetic gastropathy improvement in gastric emptying does not equate symptom relief (50). Complementary centrally acting drugs may need to be administered. For instance, some patients with severe nausea and vomiting will require concurrent central antiemetics, except if treated with a prokinetic drug with central antiemetic properties, such as metoclopramide.

Indeed, metoclopramide remains a very useful drug for the treatment of diabetic gastroparesis on account of its dual effect: central antiemetic and gastric prokinetic. However, the risk of dystonic side-effects, prolactin-related side-effects and the more remote, but fearful risk of inducing tardive dyskinesia must be considered (51). Furthermore, despite many published studies, the long-term efficacy and toxicity assessment of metoclopramide remains uncertain because many of the original studies are quite old and substandard in their methodology.

Domperidone is a peripheral D2 dopamine antagonist that lacks central toxicity effects, although it might still retain some central antinauseating properties on account of the emetic centers in the medulla being partially outside the blood-brain barrier. A comparative trial of domperidone against cisapride in children with diabetes mellitus and gastroparesis concluded that domperidone was more effective (52). Despite its lack of central antiemetic properties, cisapride was until recently a broadly used and apparently effective agent, but has been de facto removed from the market because of the risk of inducing cardiac arryhtmia (32). Cinitapride is an analogous drug available in some countries and seemingly safe.

Erithromycin, a motilin receptor agonist, is a highly effective prokinetic agent, particularly when administered as iv boluses in acute flare-ups of gastroparesis. It induces a sweeping gastric peristaltic contraction, which empties retained content into the small bowel. Unfortunately, its mid- and long-term efficacy when given orally has been cast into doubt. In addition, concerns have arisen about recommending sustained antibiotic administration. Newer motilin agonists devoid of antibiotic properties are under development. Two such molecules, KC 11458 and ABT-229 have been subjected to clinical trail, but neither has shown much efficacy in the clinical setting (53,54). Further molecules also with motilin agonist properties are at the preclinical stage.

Other pharmacological approaches are worth considering. Clonidine, an a-2 adren-ergic agonist, has been proposed on a clinical basis, but a recent trial against placebo failed to show any meaningful prokinetic effect in a group of patients with diabetic gastroparesis (55). Sildenafil, a phosphodiesterase-5 inhibitor with some positive effects on esophageal spasm has been tried to counteract pyloric spasm in diabetic gastropare-sis, but preliminary results are not too encouraging (56). With similar objectives, namely achieving sustained pyloric relaxation, botulinum toxin injection into pyloric muscle through endoscopy has been tried with some success (57-59), but series are small and follow-up quite short. Botox effects are temporary anyway.

Gastric pacing is a relatively new treatment modality which holds promise. Gastric stimulation devices are surgically implanted, first temporarily and, permanently if patients show positive responses. Several series have been published and report substantial improvement in nausea and vomiting in association with improved quality of life (60,61). Interestingly, despite symptomatic improvement, gastric emptying rates are either not accelerated or only modestly accelerated. Nutritional parameters do tend to improve. Hospital admission also decreases (62,63). On balance, gastric pacing is a potential option for patients who fail or cannot tolerate pharmacological treatment. So caution must be exerted before recommending it because evidence in favor of this method is not yet conclusive.

Psychological care of patients with symptomatic diabetic gastroparesis is of utmost importance as many of the symptoms associated with this condition are aggravated by anxiety. In truly desperate situations, subtotal gastrectomy with Roux-en-Y loop anastomosis has been undertaken to relieve intractable vomiting and its metabolic consequences (64).

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